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The purpose of the present study was to identify the roles of the three nitric oxide synthase (NOS) isoforms on whole body ischemia-reperfusion injury during cardiopulmonary resuscitation (CPR) with periodic acceleration (pGz) in pigs. Thirty-two anesthetized pigs (27.6+/-3.4 kg) were monitored for hemodynamics and selected echocardiographic variables. Twenty minutes after NOS inhibition or placebo administration, ventricular fibrillation (VF) was induced and remained untreated for 3 min, followed by CPR with pGz for 15 min, plus 3 min of manual chest compressions and defibrillation attempt. Four groups were studied: (1) saline control; (2) L-NAME (non-selective NOS inhibitor); (3) aminoguanidine (inducible NOS inhibitor); (4) TRIM (neuronal NOS inhibitor). Return of spontaneous circulation (ROSC) to 180 min occurred in 6/8 controls, 4/8 L-NAME, 7/8 aminoguanidine, and 2/8 TRIM animals. The L-NAME group had significantly lower organ blood flow, impaired cardiac function, but higher vascular tone than control group. The aminoguanidine group had the highest organ blood flows and survival rate. Six out of eight TRIM treated animals had initial return of heartbeat; however, with impaired heart contractility and could not survive more than 20 min of ROSC. This study reveals the differential role of endogenous NO produced from the three NOS isoforms during pGz-CPR. Both endothelial and neuronal NOS derived NO show predominantly protective effects while inducible NOS derived NO plays a detrimental role in pGz-CPR. The present study has shown that cardiac arrest and resuscitation appears to be associated with a different expression of NOS isoforms which appear to affect resuscitation outcomes differently. 相似文献
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OBJECTIVES: Ceftobiprole is a novel broad-spectrum cephalosporin with good in vitro activity against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. The objective of this study was to assess the in vivo activity of ceftobiprole against four strains of E. faecalis, including beta-lactamase- producing (Bla+) and vancomycin-resistant strains. METHODS: Mice were infected intraperitoneally with strains of E. faecalis: (i) the Bla+ strain HH22; (ii) two vancomycin-resistant strains (TX2484 and V583); and (iii) OG1RF (a laboratory strain), using 10 x the LD50 for each strain. Ceftobiprole doses of 25, 12.5 and 6.25 mg/kg (single doses) and ampicillin 50, 25, 12.5 and 6.25 mg/kg (single and double doses) were administered subcutaneously immediately after bacterial challenge and mice were monitored for 96 h. RESULTS: All four E. faecalis had ceftobiprole MICs 100 mg/kg, whereas ceftobiprole was protective (PD50 of 2 mg/kg). Ceftobiprole PD50s for vancomycin-resistant isolates TX2484 and V583 were 7.7 and 5.2 mg/kg, respectively, similar to those of single dose ampicillin (12.5 and 16.4 mg/kg, respectively). For OG1RF, both ampicillin and ceftobiprole protected all mice at doses of 25 and 12.5 mg/kg, respectively, with a PD50 of 4.2 and 8 mg/kg for ceftobiprole and ampicillin, respectively. CONCLUSIONS: Ceftobiprole had comparable in vivo activity to that of ampicillin against vancomycin-resistant and ampicillin-susceptible strains of E. faecalis in the mouse peritonitis model. Ceftobiprole was superior in vivo to ampicillin against the Bla+ strain HH22. Our data support the further study of ceftobiprole as a therapeutic agent in humans infected with E. faecalis. 相似文献
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Guanethidine and related agents: III. Antagonism by drugs which inhibit the norepinephrine pump in man 下载免费PDF全文
Jerry R. Mitchell John H. Cavanaugh Luis Arias John A. Oates 《The Journal of clinical investigation》1970,49(8):1596-1604
Antagonism of the antihypertensive action of guanethidine by the tricyclic antidepressants, desipramine and protriptyline, has been demonstrated in controlled studies. These antidepressants also prevent the effect of the related ring-substituted guanidinium adrenergic neuron blockers, bethanidine and debrisoquin. That the rise in blood pressure when desipramine is added to guanethidine therapy is not due simply to a pressor action of the two drugs in combination was demonstrated by the lack of an increase in blood pressure when guanethidine was added to desipramine therapy.Investigations were conducted to determine whether antagonism of guanethidine's clinical effect could result from blockade by the tricyclic antidepressants of the norepinephrine pump in the adrenergic neuron membrane, thereby preventing the uptake of guanethidine into the neuron by this pump. Like guanethidine, the indirectly acting pressor amine, tyramine, enters the neuron via the norepinephrine pump. Desipramine, protriptyline, and amitriptyline in clinical doses all were found to block the pressor action of tyramine while potentiating the pressor effect of norepinephrine. The amino acid, methyldopa, does not enter the neuron via the norepinephrine pump, and its antihypertensive action is not altered by concomitant administration of tricyclic antidepressants. It is concluded from the evidence in this investigation together with the results of previous studies in experimental animals that clinical doses of desipramine-like drugs inhibit the norepinephrine pump in the peripheral adrenergic neuron in man and thereby prevent uptake of guanethidine to its site of action. 相似文献
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Nitric oxide synthase isoform inhibition before whole body ischemia reperfusion in pigs: Vital or protective? 总被引:3,自引:1,他引:3
BACKGROUND: Nitric oxide (NO) is a critical regulator of vascular tone, and signal transduction. NO is produced via three unique synthases (NOS); endothelial (eNOS), and neuronal (nNOS) are both constitutively expressed and inducible (iNOS) produced primarily after stimulation. NO has been implicated during and after ischemia reperfusion injury as both a detrimental and cardioprotective mediator. Since cardiopulmonary resuscitation (CPR) in ventricular fibrillation (VF) is a model of whole body ischemia reperfusion injury, it provides an opportunity to assess the effects of NO from the three NOS isoforms. OBJECTIVE: To determine the differential role of nitric oxide synthase isoforms inhibition in ventricular fibrillation CPR and investigate whether inhibition of the NOS isoforms afford any cardioprotection in this model. METHODS: Thirty-two pigs, weight range 25-35 kg, were assigned to four groups of eight animals each. The animals were randomized to receive (1) N(G)-nitro-L-arginine methyl ester (LNAME), a non-selective endothelial nitric oxide synthase inhibitor, (2) 1-(2-trifluoromethylphenyl) imidazole (TRIM), a selective neuronal NOS inhibitor, (3) aminoguanidine (AMINOG), a selective inducible NOS inhibitor or (4) saline control (Control) in equal volumes, 30 min before induction of ventricular fibrillation (VF). After 3 min VF with no intervention, the animals received standard chest compressions using an automated chest compression device (Thumper) for 15 min. After 18 min of VF, single doses of vasopressin and bicarbonate were given and defibrillation attempted. Hemodynamics, regional blood flows, and echocardiography and were performed, before and after drug infusion, during CPR, and after return of spontaneous circulation (ROSC). RESULTS: ROSC for 3 h occurred in 5/8 (63%), 1/8 (13%), 0/8 (0%), and 6/8 (75%) in Control, LNAME, TRIM, and AMINOG treated animals, respectively. After infusion of LNAME, there was a significant increase from baseline in blood pressure [127+/-6 mmHg versus 169+/-3 mmHg, p<0.002] and coronary perfusion pressure [119+/-6 mmHg versus 149+/-6 mmHg, p<0.003]. During CPR, there were no differences among groups in hemodynamics or regional blood flow. In surviving animals, AMINOG had significantly better myocardial function (left ventricular ejection fraction, fractional shortening, and wall motion score index) than control or LNAME treated animals, and attenuated the post-resuscitation hyperemic response in heart and brain. CONCLUSIONS: Intact basal nNOS activity is vital for survival from whole body ischemia reperfusion injury. iNOS inhibition prior to ischemia reperfusion, protects myocardial function after ROSC and decreases myocardial and brain hyperemic response after ROSC. 相似文献
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Laura Albentosa-Gonzlez Nereida Jimenez de Oya Armando Arias Pilar Clemente-Casares Miguel ngel Martin-Acebes Juan Carlos Saiz Rosario Sabariegos Antonio Mas 《Viruses》2021,13(5)
Arthropod-borne flaviviruses, such as Zika virus (ZIKV), Usutu virus (USUV), and West Nile virus (WNV), are a growing cause of human illness and death around the world. Presently, no licensed antivirals to control them are available and, therefore, search for broad-spectrum antivirals, including host-directed compounds, is essential. The PI3K/Akt pathway controls essential cellular functions involved in cell metabolism and proliferation. Moreover, Akt has been found to participate in modulating replication in different viruses including the flaviviruses. In this work we studied the interaction of flavivirus NS5 polymerases with the cellular kinase Akt. In vitro NS5 phosphorylation experiments with Akt showed that flavivirus NS5 polymerases are phosphorylated and co-immunoprecipitate by Akt. Polymerase activity assays of Ala- and Glu-generated mutants for the Akt-phosphorylated residues also indicate that Glu mutants of ZIKV and USUV NS5s present a reduced primer-extension activity that was not observed in WNV mutants. Furthermore, treatment with Akt inhibitors (MK-2206, honokiol and ipatasertib) reduced USUV and ZIKV titers in cell culture but, except for honokiol, not WNV. All these findings suggest an important role for Akt in flavivirus replication although with specific differences among viruses and encourage further investigations to examine the PI3K/Akt/mTOR pathway as an antiviral potential target. 相似文献